International Patent Application PCT/US02/20471 having an international filing date of 26 Jun. 2002, and published as WO 03/02531 on 9 Jan. 2003, discusses serine proteases including Dipeptydyl Peptidase IV (DPP IV) and compounds that demonstrate activity as inhibitors of DPP IV. This published application, which is herein incorporated by reference, discloses heterocyclic compounds, including (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile hydrochloride.
As noted in the above-referenced publication, the (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile hydrochloride demonstrates inhibition activity of DPP IV. Problems exist with several salts forms of this compound, however, due to the absorption of very large amounts of water at commercially expected exposure humidities if utilized in a medicament (e.g., 20-75% relative humidity (RH)).
Additionally these salts present other problems due to an inability to be isolated as crystalline solids. As a result, suitability of these salts as a commercial medicament would be compromised unless special handling and storage procedures were instituted.
The present inventors have now identified a novel form (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt that is commercially suitable as a serine protease inhibitor, such as dipeptidyl peptidases inhibitor, such as DPP-IV inhibitors.
The compound of the present invention may be prepared in crystal form and therefore have enhanced physical stability. More specifically, the p-toluenesulfonic acid salt of the present invention sorbs much lower amounts of water when exposed to a broad range of humidities and can be prepared in a physically stable crystal form, thus enhancing its suitability as a medicament.